NM_014211.3:c.386T>C

Variant names:

• chr5-170795353-T-C
• rs769522365
• NM_014211.3:c.386T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014211.3(GABRP):​c.386T>C​(p.Phe129Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: GABRP NM_014211.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

Genes affected

GABRP (HGNC:4089): (gamma-aminobutyric acid type A receptor subunit pi) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. The subunit encoded by this gene is expressed in several non-neuronal tissues including the uterus and ovaries. This subunit can assemble with known GABA A receptor subunits, and the presence of this subunit alters the sensitivity of recombinant receptors to modulatory agents such as pregnanolone. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRP	NM_014211.3	c.386T>C	p.Phe129Ser	missense_variant	Exon 5 of 10	ENST00000265294.9	NP_055026.1
GABRP	NM_001291985.2	c.386T>C	p.Phe129Ser	missense_variant	Exon 5 of 9		NP_001278914.1
GABRP	XM_024446012.2	c.386T>C	p.Phe129Ser	missense_variant	Exon 5 of 10		XP_024301780.1
GABRP	XM_005265872.2	c.149T>C	p.Phe50Ser	missense_variant	Exon 3 of 8		XP_005265929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRP	ENST00000265294.9	c.386T>C	p.Phe129Ser	missense_variant	Exon 5 of 10	1	NM_014211.3	ENSP00000265294.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.386T>C (p.F129S) alteration is located in exon 5 (coding exon 4) of the GABRP gene. This alteration results from a T to C substitution at nucleotide position 386, causing the phenylalanine (F) at amino acid position 129 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;T;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;.;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.1	.;.;M;M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;T;T
Polyphen		1.0	.;.;D;D;D;.
Vest4		0.79, 0.80, 0.85, 0.83
MutPred		0.50		Gain of disorder (P = 2e-04);Gain of disorder (P = 2e-04);Gain of disorder (P = 2e-04);Gain of disorder (P = 2e-04);Gain of disorder (P = 2e-04);Gain of disorder (P = 2e-04);
MVP		0.94
MPC		0.76
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769522365; hg19: chr5-170222357;